The Hepatitis C Virus (HCV) is the leading cause of chronic hepatitis, which can progress to liver fibrosis leading to cirrhosis, end-stage liver disease, and HCC (hepatocellular carcinoma), making it the leading cause of liver transplantations. Current anti-HCV therapy, based on (pegylated) interferon-alpha (IFN-α) in combination with ribavirin, suffers from limited efficacy, significant side effects, and is poorly tolerated in many patients. This prompted the search for more effective, convenient and better-tolerated therapy.
Replication of the genome of HCV is mediated by a number of enzymes, amongst which is HCV NS3 serine protease and its associated cofactor, NS4A. Various agents that inhibit this enzyme have been described. WO 05/073195 discloses linear and macrocyclic NS3 serine protease inhibitors with a central substituted proline moiety and WO 05/073216 with a central cyclopentane moiety. Amongst these, the macrocyclic derivatives are attractive by their pronounced activity against HCV and attractive pharmacokinetic profile.
WO 2007/014926 describes macrocyclic cyclopentane and proline derivatives including the compound of formula I, with the structure represented hereafter. The compound of formula I is a very effective inhibitor of the HCV serine protease and is particularly attractive in terms of pharmacokinetics. Due to its favourable properties it has been selected as a potential candidate for development as an anti-HCV drug. Consequently there is a need for producing larger quantities of this active ingredient based on processes that provide the product in high yield and with a high degree of purity. WO 2008/092955 describes processes and intermediates to prepare the compound of formula I.

According to WO 2007/014926 the compound of formula I can be prepared starting from the bicyclic lactone carboxylic acid referred to as compound 39 in example 4, or in the general description of this reference as compound 17b, or as compound II in this description and claims. The carboxylic acid in bicyclic lactone carboxylic acid is coupled with N-methylhex-5-enylamine 38, followed by lactone opening to 4-hydroxy-cyclopentane derivative 41. The latter derivative 41 is then coupled with aminocyclo-propylcarboxylic ester to cyclopentane dicarboxylic acid diamide 43, which is coupled with quinoline 36 in an Mitsunobu ether-forming reaction, which involves an inversion at the hydroxy-bearing carbon. The resulting intermediate 44 is cyclized via a metathesis reaction to a macrocyclic derivative, in which the ester group is hydrolysed and coupled with cyclopropylsulfonylamide to yield the desired end product of formula I. These reactions are illustrated in the following scheme in which R represents C1-4alkyl and in example 4, R is ethyl.

The enantiomercally pure bicyclic lactone 39 was prepared starting from an enantiomer of 3,4-bis(methoxycarbonyl)cyclo-pentanone, referred to as (17a) in WO 2007/014926. The latter was prepared as described by Rosenquist et al. in Acta Chemica Scandinavica 46 (1992) 1127-1129. Racemic cyclohexene dicarboxylic acid methyl ester was synthesized via a Diels-Alder reaction of 3-sulfolene and dimethyl fumarate, followed by oxidative cleavage of the double bond, cyclization, and decarboxylation, resulting in (±) 4-ketocyclopentane dicarboxylic acid dimethyl ester. Resolution of the latter by hydrolysis using pig liver esterase resulted in the corresponding (+)-monoacid and the (−) diester, which is intermediate (17a) of WO 2007/014926.

After removal of the (+)-monoacid, the trans (3R,4R)-3,4-bis(methoxycarbonyl) cyclopentanone diester (17a) was converted to the bicyclic lactone 17b (also referred to as compound II, see above), first by a keto to alcohol reduction, followed by hydrolysis of the esters, and lactone formation.
The synthesis procedure for preparing I described in WO 2008/092955 starts from an intermediate D, wherein the ester function is hydrolysed, and coupled with cyclopropyl amino acid ester C. The resulting intermediate B is cyclized by an olefin metathesis reaction to the macrocyclic ester A, which is hydrolyzed and coupled with cyclopropylsulfonylamide to the end product I. These reactions are outlined in the reaction scheme below. In this and the following reaction schemes R is C1-4alkyl, in particular R is ethyl. R1 is C1-4alkyl, in particular R1 is methyl or ethyl.

Intermediate D in turn can be prepared starting from a hydroxycyclopentyl bis-ester of formula H1, by either    (a) reacting H1 with a thiazolyl substituted quinolinol E to the quinolinyloxy-cyclopentyl bis-ester of formula K, followed by a cleavage of the benzyl ester group to the mono-carboxylic acid J, which in turn is coupled with an N-methyl hexenamine to intermediate D; or    (b) cleaving the benzyl ester in H1 to the mono-carboxylic acid G, coupling the latter with an N-methyl hexenamine to the hydroxycyclopentylamide F, which in turn is reacted with E, thus obtaining D; as outlined in the following reaction scheme:

Each R1 is in this scheme is as specified above and Bn represents benzyl.
WO 2008/092955 furthermore describes procedures for preparing intermediate H1 starting from 4-oxo-1,2,-cyclopentanedicarboxylic acid O, by a keto to alcohol reduction, thus obtaining 4-hydroxy-1,2-cyclopentanedicarboxylic acid N, which in turn is cyclized to the bicyclic lactone M. Esterification of the carboxylic acid group in the latter yields the lactone benzyl ester L, wherein the lactone is opened by a transesterification reaction in the presence of a C1-4alkanol, thus yielding intermediate H, which is resolved in its enantiomers H1 and H2, as outlined in the following reaction scheme:

A disadvantage of the above process is that it involves a resolution of the enantiomers of H by chiral column chromatography, a cumbersome procedure that is difficult to run at large scale production. Another disadvantage is that the resolution takes place at a later stage of the synthesis, whereby half of the building block H has to be discarded. The presence of various chiral centers in the compound of formula I and its predecessors poses particular challenges in that enantiomeric purity is essential to have a product that is acceptable for therapeutic use. Hence the processes for preparing D should result in products of acceptable enantiomeric purity without use of cumbersome purification procedures with the loss of substantial amounts of undesired stereoisomeric forms.
Honda et al. Tetrahedron Letters, vol. 22, no. 28, pp 2679-2682, 1981, describes the synthesis of (±)-brefeldin A, using the following starting materials:

The synthesis of Honda et al. starts from dl-trans-4-oxocyclopentane-1,2-dicarboxylic acid 2, which was esterified to the corresponding methyl ester 3, and reduced with Raney-Ni to the alcohol 4. Partial hydrolysis of 4 to the monocarboxylic acid and benzylation with benzyl bromide gave predominantly diastereoisomer 5, namely the diastereoisomer wherein the hydroxy and benzyl ester groups are in cis position. The latter ester 5 in Honda et al. and compound H are both racemates, but are diastereoisomers of one another, more precisely epimers on the carbon no. 4 bearing the hydroxy group. Compound H1 is one of the two enantiomers obtained by separation from the racemic compound H. The other enantiomer is compound H2.
The bicyclic lactone (17b) is an interesting building block in the synthesis of the compound of formula I. Finding a synthesis path to obtain this lactone in good yield and high enantiomeric purity is a desirable goal to achieve. The present invention provides such a process.
WO 2010/072742 describes the use of the cinchonidine salt of the aforementioned bicyclic lactone as an intermediate in the preparation of intermediate (IX), and therefore also in the preparation of the HCV inhibitor (I).

In WO 2010/072742, the cinchonidine salt (IV) is prepared via the resolution of a diastereoisomeric salt mixture (III) by selective crystallization. The salt (III) in turn is obtained by forming the cinchonidine salt of the racemic bicyclic lactone carboxylic acid (II), as outlined in the following reaction scheme:

It is desired to provide a more convenient process for preparing the cinchonidine salt (IV).